Combination vaccines including antigens for immunising against diphtheria, tetanus, pertussis and Hib are known (‘DTP-Hib’ vaccines). Three such vaccines have been marketed under the names TETRAMUNE™ and QUATTVAXEM™ (which use cellular pertussis antigens ‘DTwP-Hib’) and INFANRIX-Hib™ (which uses acellular pertussis antigens ‘DTaP-Hib’).
The inclusion of Hib-conjugate components in DTaP-Hib vaccines has been associated with reductions in the anti-Hib response [1, 2]. Furthermore, Hib-conjugates are unstable in aqueous media and cannot survive prolonged storage in this form [3]. For this reason, in combination vaccines that include Hib-conjugate antigens, it is common for the Hib component to be provided as a lyophilised powder that is reconstituted at the time of delivery with a liquid formulation of the other antigens.
Hib-conjugate antigens are not cheap to produce, and there is concern that their cost will inhibit widespread use in developing countries, and so alternative strategies for Hib-conjugate use have been developed [4-6]. One approach to furthering their use has been to give two doses (e.g. at 3 & 5 months of age [5] or at 4 & 6 months [6]), rather than the normal three doses (2, 4 & 6 months [7]). In a different approach, whereas Hib-conjugates are typically given at 10 μg/dose, lower doses (typically fractions e.g. ½, ⅓, ¼, etc.) have been used [4, 6]. In ref. 6, for example, Hib-conjugates were administered at 5 μg/dose or 3.33 μg/dose.
The same approach has been extended to Hib-conjugates within DTP-Hib vaccines. For example, reference 8 compares full-dose, half-dose and third-dose use of Hib-conjugate in combination with a DTwP vaccine and, although geometric mean concentrations of anti-PRP bodies were reduced in patients receiving combined DTP-Hib vaccines compared to separate administration of DTP and Hib, acceptable protective anti-Hib immune responses were seen in all cases. Reference 9 uses a 10-fold dilution of Hib-conjugate dosage by reconstituting a single Hib dose with a ten-dose vial of DTwP. Reference 10 discloses reconstitution of lyophilised Hib-conjugate at full dose, half-dose or quarter-dose using the TRITANRIX™ DTwP-HBsAg vaccine.
In each of these cases, however, the Hib-conjugate was in lyophilised form and had to be reconstituted by aqueous DTP antigens prior to administration. These vaccines must thus be provided in two separate containers (aqueous DTP in one, lyophilised Hib in the other), and this double container requirement imposes additional cost and logistical requirements at the packaging stage, the transport stage, the storage stage and the administration stage. As the reduced-dose vaccines are intended to reduce cost and encourage distribution in the developing world then these additional requirements are significant disadvantages. The requirement for a reconstitution step also means that there is a risk of error by the end user, a tendency towards non-standardised dosages, a risk of contamination of the mixed product and a need to train staff in the reconstitution procedure. All of these problems frustrate the intended target market i.e. the developing world.
There thus remains a need for a combination vaccine that includes a low dose of Hib-conjugate antigen and does not need separate packaging of the Hib antigen.